Radioactive pharmaceuticals are in common use in imaging studies to aid in the diagnosis of a wide variety of illnesses including cardiac, renal and neoplastic diseases. These pharmaceuticals, known in the art as "imaging agents," typically are based on a gamma-emitting radionuclide attached to a carrier molecule or "ligand." Gamma-emitting radionuclides are the radionuclides of choice for conducting diagnostic imaging studies because, while gamma radiation is detectable with appropriate imaging equipment, it is substantially less-ionizing than beta or alpha radiation. Thus, gamma radiation causes minimal damage to targeted or surrounding tissues.
Radioactive pharmaceuticals now are finding increased use as therapeutic agents for treating neoplastic disorders, especially tumors. Therapeutic radiopharmaceuticals generally incorporate a strong beta- or alpha-emitting radionuclide, the radiation emission being useful in the treatment of certain neoplastic disorders. Such beta or alpha radiation produces intensive ionization paths within a short distance of the radioactive isotope in comparison to the gamma radiation emitted by diagnostic radionuclides, and thus is substantially more damaging to targeted cells.
While the efficacy of radioactive therapeutic agents is established, it is also well known that the emitted alpha or beta particles can cause substantial chemical damage or destabilization to various components in radiopharmaceutical preparations. Emitted alpha and beta particles can produce radiolysis, usually caused by the generation of free radicals, can precipitate proteins present in the preparations, and can cause chemical damage to other substances present in the preparations. The degradation and destabilization of proteins and other components caused by the alpha and beta emitters is especially problematic in aqueous preparations. The degradation or destabilization lowers or destroys the effectiveness of radiopharmaceutical preparations, and has posed a serious problem in the art. Gamma emissions from imaging radionuclides, by contrast, tend to be less damaging and thus are less likely to destabilize the radiopharmaceutical preparations in which they are incorporated.
For diagnostic imaging purposes, radiopharmaceuticals based on a coordination complex comprised of a gamma-emitting radionuclide and a chelate have been used to provide both negative and positive images of body organs, skeletal images and the like. The Tc-99m skeletal imaging agents are well-known examples of such complexes. One drawback to the use of these radioactive complexes is that while they are administered to the patient in the form of a solution, neither the complexes per se nor the solutions prepared from them are overly stable. Consequently, the coordination complex and solution to be administered commonly are prepared "on site," that is, they are prepared by a nuclear pharmacist or health care technician just prior to conducting the study. The preparation of appropriate radiopharmaceutical compositions is complicated by the fact that several steps may be involved, during each of which the health care worker must be shielded from the radionuclide.
The preparation of stable radiopharmaceutical therapeutic agents, due to the type of radioactivity, presents even greater problems. These agents typically are based on a relatively energetic alpha- or beta-emitting radionuclide complexed with a chelate. Frequently, the radionuclide/chelate complex is in turn bound to a carrier molecule which bears a site-specific receptor. Thus, it is known that an alpha- or beta-emitting radionuclide attached to a tumor-specific antibody or antibody fragment can destroy targeted neoplastic or otherwise diseased cells via exposure to the emitted ionizing radiation. Bi-functional chelates useful for attaching a therapeutic radionuclide to a carrier molecule such as an antibody are known in the art. See e.g. Meares et al., Anal. Biochem. 142:68-78 (1984).
For most imaging and therapeutic applications of radiopharmaceutical complexes of the types mentioned above, the nonradioactive portion(s) of the complex is prepared and stored until time for administration to the patient, at which time the radioactive portion of the complex is added to form the radiopharmaceutical of interest. For example, attempts to prepare radionuclide-antibody complexes have resulted in complexes which must be administered to the patient just after preparation because, as a result of radiolysis, immunoreactivity may decrease considerably after addition of the radionuclide to the antibody. In Mather et al., J. Nucl. Med., 28:1034-1036 (1987), a technique for labeling monoclonal antibodies with large activities of radioiodine using the reagent N-bromosuccinimide is described. The authors suggest that the antibodies labeled in this manner be administered to the patient immediately after preparation to avoid losses of immunoreactivity. Other examples of the preparation of the nonradioactive portion of the complex followed by on-site addition of the radioactive portion are disclosed in U.S. Pat. No. 3,984,227 (1976) and U.S. Pat. No. 4,652,440 (1987). Further, in many situations, the radioactive component of the complex must be generated and/or purified at the time the radiopharmaceutical is prepared for administration to the patient. U.S. Pat. No. 4,778,672 (1988) describes, for example, a method for purifying pertechnetate and perrhenate for use in a radiopharmaceutical.
EP 250,966 (1988) describes a method for obtaining a sterile, purified, complexed radioactive perrhenate from a mixture which includes, in addition to the ligand-complexed radioactive perrhenate, uncomplexed ligand, uncomplexed perrhenate, rhenium dioxide and various other compounds. Specifically, the application teaches a method for purifying a complex of rhenium-186 and 1-hydroxyethylidene diphosphonate (HEDP) chelate from a crude solution. Because of the instability of the complex, purification of the rhenium-HEDP complex by a low pressure or gravity flow chromatographic procedure is required. The purification procedure involves the aseptic collection of several fractions, followed by a determination of which fractions should be combined. After combining the appropriate fractions, the fractions are sterile-filtered and diluted prior to injection into the patient. The purified rhenium-HEDP complex should be injected into the patient within one hour of preparation to avoid the possibility of degradation. The rhenium complex may have to be purified twice before use, causing inconvenience and greater possibilities for radiation exposure to the health-care technician.
While the lyophilization process has been applied to various types of pharmaceutical preparations in the past, the notion of lyophilizing alpha- and beta-emitting radiopharmaceutical preparations has not been addressed. In part, this is believed to be due to skepticism of those skilled in the art that such a procedure could be safely carried out. U.S. Pat. No. 4,489,053 (Azuma et al.; Dec. 18, 1984) relates to Tc-99m-based diagnostic imaging agents. The patentee notes that the radioactive agents may be prepared in lyophilized form. Alpha- or beta-emitting radionuclides are not addressed, however.
Thus, there is a need in the art for a method of centrally preparing and purifying a stabilized therapeutic radiopharmaceutical for shipment to the site of use in a form ready for simple reconstitution prior to its administration in therapeutic applications. There is a particular need in the art for a method of centrally preparing and purifying radionuclide-labelled antibodies and antibody fragments, owing to their relatively instable immunoreactivities once in aqueous solution.